WO1994022424A1 - Membrane biodegradable, permeable a l'eau pour pompe a absorption de fluide - Google Patents

Membrane biodegradable, permeable a l'eau pour pompe a absorption de fluide Download PDF

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Publication number
WO1994022424A1
WO1994022424A1 PCT/US1994/003394 US9403394W WO9422424A1 WO 1994022424 A1 WO1994022424 A1 WO 1994022424A1 US 9403394 W US9403394 W US 9403394W WO 9422424 A1 WO9422424 A1 WO 9422424A1
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WO
WIPO (PCT)
Prior art keywords
membrane
fluid
recited
pump
imbibing
Prior art date
Application number
PCT/US1994/003394
Other languages
English (en)
Inventor
Patrick S.-L. Wong
Felix Theeuwes
Brian L. Barclay
Michael H. Dealey
Original Assignee
Alza Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Alza Corporation filed Critical Alza Corporation
Priority to AU65266/94A priority Critical patent/AU6526694A/en
Publication of WO1994022424A1 publication Critical patent/WO1994022424A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to controlled agent delivery devices. More particularly, this invention relates to orally administered fluid- imbibing pump devices for gastrointestinal drug delivery. Still more particularly, this invention relates to water-permeable, biodegradable membranes for fluid-imbibing pumps.
  • Delivery agents are used interchangeably herein to refer to any substance which is delivered to a living organism or plant to produce a desired, usually beneficial, effect.
  • Many forms of controlled drug delivery devices are currently being practiced and further developed. Examples of such drug delivery devices include intravenous devices such as in U.S. 4,857,052, transdermal devices such as in U.S. 4,725,272, electrotransport devices such as in U.S. 5,080,646, and osmotic pump devices such as in U.S. 3,916,899. Many of these devices employ coatings, films, or membranes which function as a means of controlling the drug delivery rate.
  • a fluid-imbibing pump also referred to as an osmotic pump, is one type of device which utilizes one or more membranes in controlling drug delivery rates.
  • “fluid-imbibing pump” refers to a device which imbibes fluid from the surroundings through a membrane, thereby generating an internal pressure useful in expelling a substance from within the membrane.
  • One type of fluid-imbibing pump commonly referred to as an elementary osmotic pump, generates an internal pressure when water surrounding the device diffuses through the semi- permeable membrane and dissolves the drug.
  • the driving force for osmosis, or water diffusion into the device is the drug concentration gradient across the membrane.
  • the membrane is impermeable to drug, more water diffuses into the device than out of the device, thereby generating a pressure sufficient to deliver drug solution through one or more orifices in the membrane.
  • Another type of fluid-imbibing pump does not require water-soluble agent to function. In these devices, water diffusing across a semi-permeable membrane contacts a hydrophilic polymer. The hydrophilic polymer expands upon contact with water, thereby generating a pressure inside the device sufficient to deliver drug through one or more orifices in the membrane.
  • Biodegradation relates to the chemical and/or mechanical degradation resulting in disintegration of a membrane upon exposure to animal body fluids, e.g. gastrointestinal (Gl) fluids.
  • fluid-imbibing pumps either are designed to be naturally expelled from an animal or are designed to be manually removable.
  • problems may arise when a pump is neither naturally expelled or manually removable after drug delivery has ceased.
  • an orally administered pump will pass through a human gastrointestinal system in less than about 24 hours, it is possible for a device to become lodged in the Gl tract.
  • the membrane In order to eliminate remnants of the fluid-imbibing pump after the useful life has expired, it would be desirable for the membrane to disintegrate after delivery is accomplished. Therefore, an improved membrane for an fluid- imbibing pump would biodegrade at a predetermined time after exposure to body fluids, thereby diminishing the structural integrity of the membrane to a point at which the membrane separates or ruptures.
  • Biodegradable materials known in the drug delivery art include poly(d,l-lactide-co-glycolide) copolymers, as disclosed in U.S. 4,897,268 and "Biodegradable Polymers as Drug Delivery Systems", Drugs and the Pharm. Sci., vol. 45, ch. 1 (1990).
  • Poly(d,l-lactide-co- glycolide), also referred to as polydactide-glycolide) or PLG is used herein to describe generally copolymers of lactic and glycolic acids.
  • polydactide-glycolide) copolymers are biodegradable, these copolymers allow insufficient water permeability for use as membranes for fluid-imbibing pumps.
  • hydrophilic polymers such as cellulose acetates
  • cellulose acetates are known for use in membranes of osmotic delivery devices, as disclosed in U.S. 3,916,899.
  • Such hydrophilic polymers are useful in allowing water permeation into the device while preventing drug permeation out of the device, except through pre-formed orifices in the membrane.
  • hydrophilic polymers do not biodegrade at a sufficient rate to function as a biodegradable membrane for a fluid-imbibing pump.
  • a biodegradable, water-permeable membrane for a fluid-imbibing pump which disintegrates after exposure to gastrointestinal fluids for a predetermined time.
  • a method is needed for forming a water-permeable membrane for an osmotic drug delivery device which will disintegrate after a predetermined time of exposure to Gl fluids.
  • the pump includes a core comprising a delivery agent.
  • the core is at least partially enclosed by a biodegradable, water-permeable membrane.
  • the membrane has sufficient water permeability and structural integrity to deliver the agent during a predetermined period.
  • Membrane structural integrity decreases with time of exposure to gastrointestinal fluids.
  • Structural integrity decreases to the point at which the membrane disintegrates. This disintegration occurs within about 90 days after the predetermined delivery period.
  • the biodegradable membrane is preferably formed from a hydrophilic polymer and a poly(d,l-lactide-co-glycolide) copolymer.
  • the volume further includes a hydrophilic polymer which expands upon contact with water, thereby causing a positive pressure inside the device.
  • the fluid-imbibing pump is designed for oral administration to a human. Agent delivery is initiated by surrounding water diffusing through the membrane as the pump passes through the gastrointestinal tract. Water in the gastrointestinal tract is osmotically imbibed through the surrounding membrane as a result of a concentration gradient. An agent is delivered through one or more orifices in the membrane as a result of pressure generated by water within the device and/or expansion of a hydrophilic polymer.
  • the polydactide-glycolide biodegrades, thereby allowing the membrane to disintegrate and the residual device contents to disperse. This minimizes lodging of solid remnants of the device in the gastrointestinal tract.
  • FIGURE 1 is a schematic side view of one embodiment a fluid-imbibing pump of the present invention prior to agent delivery. This embodiment illustrates use of a hydrophilic polymer delivery means.
  • FIGURE 2 is a schematic side view of the device of FIG. 1 wherein agent delivery has been initiated.
  • the fluid-imbibing pump of the present invention employs a biodegradable, water-permeable membrane which biodegrades in the gastrointestinal tract.
  • the membrane comprises poly(d.l-lactide-co-glycolide), also referred to as polydactide-glycolide) or PLG, and a hydrophilic polymer.
  • the hydrophilic polymer component allows water passage through the membrane which activates the agent delivery mechanism, while the polydactide-glycolide) component degrades upon exposure to gastrointestinal fluids, thereby effectively disintegrating the membrane after a predetermined time. This biodegradation of the membrane minimizes potential problems associated with device lodging in the delivery environment, e.g. in crevices of the Gl tract.
  • one embodiment of the fluid-imbibing pump 10 of the present invention includes a agent distribution means 12, a delivery agent 14, and a rate-controlling semipermeable membrane 16 having at least one delivery orifice 18, which is sized to permit agent distribution at the desired rate, as illustrated in FIG. 1.
  • the agent distribution means 12 is composed of at least one hydrophilic polymer.
  • the semipermeable membrane 16 surrounds or encapsulates the agent distribution means 12 and the agent 14.
  • the semipermeable membrane 16 must be permeable to surrounding water to some extent, while impermeable to agent passage.
  • the semipermeable membrane of the present invention is biodegradable, i.e., the membrane decomposes or disintegrates over a predetermined time period of exposure to gastrointestinal fluids.
  • a delivery orifice 18 is formed through the semipermeable membrane 16. The orifice 18 must be sufficiently large to allow agent passage at the desired delivery rate.
  • the agent layer 14 is positioned adjacent to the delivery orifice 18. Although the agent 14 is commonly in solid form, a liquid form of the agent may be utilized.
  • Agent delivery is initiated when water penetrates the membrane 16 because of the agent and/or polymer concentration gradient between inside and outside the device. As water diffuses through the semipermeable membrane 16, solid agent 14 may be dissolved. Agent 14 is delivered to the surroundings through the delivery orifice 18 via pressure generated from the expanding hydrophilic polymer in the delivery means 12. The rate of water influx is controlled by proper selection of the composition, thickness, porosity, and surface area of the semipermeable rate-controlling membrane 16. Furthermore, the composition and amount of the hydrophilic polymer in the agent distribution means 12 has an impact on the agent delivery rate.
  • the membranes of the fluid-imbibing pumps of the present invention are designed so as to be biodegradable after a predetermined time.
  • Biodegradable is used herein to describe those membranes which will decompose and disintegrate over a relatively short time upon exposure to an animal gastrointestinal system.
  • Disintegration means either a separation of the membrane, caused by chemical decomposition of one or more membrane components, and/or a rupture, resulting from mechanical forces. Thus, “disintegration” describes a loss of structural integrity in the membrane which is manifested in membrane deformation, cracking, fragmentation, dissolution, and/or erosion.
  • Disintegration of the membrane allows expulsion of the membrane and associated core from the gastrointestinal tract after agent delivery is completed.
  • Exemplary of mechanical forces aiding in membrane disintegration are physical contact with the walls of the gastrointestinal tract or with particulates passing through the Gl tract.
  • mechanical forces aiding in disintegration may include a pressure differential across the membrane caused by the fluid-imbibing characteristics of the pump, such as the expansion pressure generated by the optional hydrophilic polymer distribution means.
  • Disintegration of the membranes of the present invention may occur from the time of cessation of agent delivery to about 90 days. 5 Delivery of agent preferably occurs over a period of about one to about 48 hours, more preferably about one to about 24 hours. Preferably, the structural disintegration of the membranes occurs less than about 30 days after the delivery period. More preferably, membrane disintegration occurs within about 14 days after the agent delivery o period. Disintegration of the membrane is desirable after agent delivery is completed but before problems associated with potential lodging in the Gl tract can occur.
  • the materials chosen for the membrane of the present invention must decompose at a relatively predictable rate in the human s gastrointestinal tract, i.e., the stomach and the large and small intestines.
  • the materials and corresponding degradation products cannot be toxic to humans, and preferably, do not cause any detrimental side effects, such as irritation or sensitization.
  • the biodegradable component of the membranes of this invention includes poly(d,l-lactide- o co-glycolide) copolymers. More preferably, the membrane is composed, in part, of a poly(d,l-lactide-co-glycolide) copolymer having a weight percent of lactide of about 40% to about 60%, based on total polymer weight.
  • PLG poly(d,l-lactide-co-glycolide) 5
  • hydrophilic polymer materials suitable for the membranes of the present invention include, without limitation, cellulose 0 acetates, poly(vinyl alcohol), hydrophilic polyurethane, poly(vinylpyrrolidone), h ⁇ droxypropylmethyl celluloses, h ⁇ droxyprop ⁇ l cellulose, hydroxyethyl cellulose, methylcellulose, poly(ethylene oxides), and acid carboxy polymers having a molecular weight of about 450,000 to about 4,000,000.
  • Other suitable hydrophilic polymers components of the membrane of this invention are disclosed in U.S Pat. No. 3,916,899 (Theeuwes), which is incorporated herein by reference.
  • cellulose acetate is mixed with the biodegradable material to improve water permeability.
  • Cellulose acetates having an acetate content of about 32% to about 43% by weight have preferred mechanical properties and water permeability characteristics.
  • the ratios of poly(d,l-lactide-co-glycolide) to hydrophilic polymer in the membranes may vary depending on the desired rate of water permeability and rate of membrane degradation. In order to provide a biodegradation rate of greater than about 7 days but less than about 90 days after agent delivery, and to provide sufficient water permeability to effect agent delivery, a composition of about 20% to about 60% polydactide-glycolide) and 40% to 80% hydrophilic polymer by weight, based on total membrane weight, is preferred.
  • the membrane may degrade before agent delivery is completed or water permeation rates may be insufficient to achieve desired agent delivery rates. In contrast, lower polydactide- glycolide) concentrations may result in an insufficient biodegradation rate.
  • the degradation rate of the membrane is also a function of the molecular weight of the polydactide-glycolide). Increasing the PLG molecular weight reduces the degradation rate, i.e. increases the degradation time.
  • the polydactide-glycolide has a number average molecular weight in the range of about 1000 to about 20,000.
  • the hydrophilic polymer component of the membrane may be a mixture of hydrophilic polymers.
  • the permeation rate can be modulated without affecting the overall ratio of biodegradable component, e.g. polydactide-glycolide), to hydrophilic polymer in the membrane.
  • biodegradable component e.g. polydactide-glycolide
  • PMMA poly(methyl methacrylate)
  • poly(vinylpyrrolidone) is preferred for enhancing water permeation rates in cellulose acetate membranes.
  • a preferred biodegradable, water-permeable membrane of this invention includes polydactide-glycolide), cellulose acetate, and poly(vinyipyrrolidone).
  • the preferred composition for these components is about 20% to 60% polydactide-glycolide), about 10% to 70% cellulose acetate, and about 10% to 30% poly(vinylpyrrolidone) by weight, based on total membrane weight.
  • chemical additives may be mixed with the polydactide-glycolide) and hydrophilic polymer, for example, to improve the processing characteristics, structural stability, or aesthetic appeal of the biodegradable, water-permeable membrane.
  • binders or colorants may be added to the membrane forming mixture. Suitable binders are disclosed in U.S. Pat. No. 4,135,514, which is incorporated herein by reference.
  • Elongation or “elongation at break”, as used herein, refer to the increase in a membrane dimension from the point of initial load application to the point of membrane rupture in a tension test, typically expressed as a percentage increase.
  • the measurement of elongation at break of the membrane may be determined by commercially available instrumentation, such as the Instron Universal Testing Instrument, model no. TM-S, available from Instron Corp., Instron, Massachusetts.
  • the membranes of the present invention preferably have an elongation at break of less than about 10% of the original membrane dimension. More preferably, the elongation at break is less than about 4%.
  • the elongation at break is less than about 2%.
  • Another factor relating to disintegration of the membrane in the gastrointestinal tract is the tensile strength at break.
  • the initial membrane tensile strength at break is preferably about 1 x 10 '3 psi to about 10 x 10 '3 psi.
  • Tensile strength may be measure by a variety of means, more preferably by an Instron Universal Testing Instrument. Exposure of the membrane to gastrointestinal fluids causes degradation of the membrane, thereby reducing the tensile strength. Within about 90 days after the delivery period, the tensile strength at break is preferably less than about 1 x 10 "3 psi.
  • the membranes of the present invention may be applied by any means known in the art.
  • Some methods of coating an osmotic device of the present invention involve first dissolving the poly(d,l-lactide- co-glycolide) and selected hydrophilic polymer in a solvent.
  • the membrane components preferably represents about 1 % to about 10% by weight of the resulting mixture. More preferably, the membrane components represent about 3% to about 5% by weight of the resulting mixture.
  • the resulting mixture may be applied to the osmotic device by such processes as spray coating, dip coating, or air suspension coating.
  • Air suspension coating processes may be preferred due to a balancing of factors, including economic and coating precision concerns.
  • the air suspension procedure is disclosed in U.S. Pat. No. 3,207,824 and in J. Am. Pharm. Assoc, vol. 48, pp. 451-59 (1958) and vol. 49, pp. 82-84 (1960). These references are hereby incorporated by reference.
  • Commercially available air suspension coaters include the WURSTER ® and AEROMATIC ® coat
  • the solvents chosen for dissolving the polydactide-glycolide) and membrane hydrophilic polymer should not react substantially with the selected agent or hydrophilic polymer of the agent delivery means.
  • the selection of solvent is also dependent upon the rate of solvation of the poly(d,l-lactide-co-glycolide) and hydrophilic polymer to be incorporated in the membrane.
  • suitable solvents include, without limitation, ethylene chloride, ethanol, methylene chloride, methanol, water, and mixtures thereof. More specifically, methylene chloride/methanol, ethylene chloride/methanol and acetone/water mixtures are preferred solvents for poly(d,l-lactide-co-glycolide) and cellulose acetate membrane coating formulations.
  • the membranes of the present invention have a thickness of about 0.001 to about 0.025 inches (about 25 to about 625 microns). Membrane thicknesses of about 0.002 inches to about 0.010 inches (about 50 to about 250 microns) are more preferred.
  • one or more delivery orifices are formed in an area of the membrane adjacent to the agent layer.
  • the orifices or holes may be formed by any available means, including mechanical drilling, punching, and laser drilling. Laser drilling is usually preferred for precision and accuracy reasons. It is also possible to form the orifices in situ by processes which include the step of forming the membrane around a removable mold, wire, fiber or the like, which is subsequently removed from the membrane. Examples of such processes are disclosed in U.S. Pat. No. 3,916,899, which is herein incorporated by reference.
  • the minimum delivery orifice area is an area large enough to permit sufficient flow of agents and excipients out of the device to achieve desired agent delivery rates. Also, inadequate orifice dimensions may cause excessive pressure resulting in premature membrane rupture. Discussion of the variables affecting delivery orifice sizing are more fully discussed in U.S. Pat. No. 3,916,899, which is incorporated herein by reference. Typically, the preferred orifice diameter of the semi-permeable membrane will range from about 0.4 mm to about 1.0 mm.
  • agent or drug
  • drug are used interchangeably and are intended to have their broadest interpretation as any substance which is delivered to a living organism to produce a desired, usually beneficial, effect.
  • this includes therapeutic agents in all of the major therapeutic areas including, but not limited to, anti-infectives such as antibiotics and antiviral agents; analgesics such as fentanyl, sufentanil, and burprenorphine, and analgesic combinations; anesthetics; anorexics; antiarthritics; antiasthmatic agents such as terbutaline; anticonvulsants; antidepressants; antidiabetics agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antimotion sickness preparations such as scopolamine and ondansetron; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics including gastrointestinal and urinary; anticholinergics; sympathomimetrics; xanthine derivatives; cardiovascular preparations including calcium channel blockers such as nifedipene; beta-agonists, cor
  • agent delivery may be accomplished without a separate agent delivery means.
  • the fluid- o imbibing pump could consist solely of a biodegradable, water-permeable membrane surrounding a water soluble delivery agent.
  • agents that are very soluble in water and that can be delivered by the devices of this invention include nystatin, chlorhexidine, clonidine, sodium fluoride, prochlorperazine adisylate, ferrous sulfate, aminocaproic acid, potassium s chloride, mecamylamine hydrochloride, amphetamine sulfate, benzphetamine hydrochloride, isoproterenol sulfate, methamphetamine hydrochloride, phenmetrazine hydrochloride, bethanechol chloride, methacholine chloride, pilocarpine hydrochloride, atropine sulfate, methascopolamine bromide, isopropamide iodide
  • agents having poor solubility include nicotine base, retin A, ibuprofen, diphenidol, meclizine hydrochloride, prochlorperazimine maleate, phenoxybenzamine, thiethylperazine maieate, anisindone, diphenadione erythrityl tetranitrate, dizoxin, isofuraphate, reserpine, o acetazolamide, methazolamide, bendrofiumethiazide, chlorpropamide, tolzamide, chlormadinone acetate, phenaglycodol, allopurinol, aluminum aspirin, methotrexate, acetyl sulfisoxazole
  • agents that can be delivered by the fluid-imbibing pump of the present invention include, without limitation, aspirin, indomethacin, naproxen, fenoprofen, sulidac, diclofenac, ibuprofen, indoprofen, nitroglycerin, propranolol, metoprolol, valproate, oxprenolol, timolol, atenolol, alprenolol, cimetidine, clonidine, imipramine, levodopa, chlorpromazine, reserpine, methyl-dopa, dihydroxyphenylalanine, pivaloyloxyethyl ester of ⁇ -methyldopa hydrochloride, theophylline, calcium gluconate, ferrous lactate, vincamine, diazepam, phenoxybenzamine, ⁇ -blocking agents, polypeptides, proteins, and the
  • the optional osmotic delivery means 12 of the present invention is a material which absorbs water, thereby expanding and causing a pressure increase inside the delivery device. This expansion pressure causes or enhances agent delivery through the delivery orifice(s) 18.
  • this material is a hydrophilic polymer comprising noncross- linked hydrogels and lightly cross-linked hydrogels, such as those cross- linked by covalent or ionic bonds. These hydrophilic hydrogels exhibit about a 2 to 50 fold volume increase.
  • Suitable hydrophilic polymers useful in agent delivery means according to the present invention include, without limitation, acidic carboxy polymers having a molecular weight of about 450,000 to about 4,000,000; poly(hydroxyalkyl methacrylate) polymers having a molecular weight of about 30,000 to about 5,000,000; poly(vinyl pyrrolidone) polymers having a molecular weight of about 10,000 to about 360,000; polyacrylic acid having a molecular weight of about 80,000 to about 200,000; polyethylene oxide) polymers having a molecular weight of about 100,000 to about 5,000,000, and the like.
  • Representative polymers that form hydrogels and that are useful as agent delivery means in the present invention are disclosed in U.S. Pat. Nos.
  • this invention is not limited to those fluid-imbibing pumps having a delivery means separate from the delivery agent to be delivered.
  • the membranes of the present invention are also useful in those fluid-imbibing pumps consisting of a water soluble agent surrounded by the membrane, i.e. in absence of a hydrophilic polymer delivery means.
  • These delivery devices are also referred to as elementary osmotic pumps.
  • a coating solution was prepared by dissolving poly(d,l-lactide-co-glycolide) (50:50), having a number average molecular weight of about 10,000, and cellulose acetate in about equal weight portions in a methylene chloride:methanol solvent (80:20 weight ratio) using about a six hour mixing time.
  • the resulting solution contained about 3% by weight poly(d,l-lactide-co-glycolide) and cellulose acetate.
  • Films were formed on one inch diameter plastic disks using an Aeromatic Coater (a modification of model STREA-1 ). About 400 gram, 5/16 inch (about 7.94 mm) diameter saccharide cores were used as fillers.
  • the resulting film thicknesses ranged from about 0.005 to about 0.012 inches (about 127 to 305 microns). Films were dried overnight at about 50 °C.
  • the films were continuously immersed in artificial gastric fluid (no enzymes) at about 37 °C.
  • An Instron Universal Testing Instrument was utilized to determine modulus, tensile stress at break and percent elongation at 0, 1 , 2, 3, 4, and 7 days after immersion in gastric fluid.
  • TABLE 1 demonstrates that the elongation at break for the poly(lactide-glycolide)/cellulose acetate membranes ranged from about 3% to about 6% of the initial membrane length.
  • Three water permeability enhancement additives i.e. hydrophilic polymers, were evaluated in conjunction with poly(d,l-lactide- co-glycolide) and cellulose acetate membranes.
  • the weight percentage of the membranes were about 40% polydactide-glycolide), 40% cellulose acetate, and 20% permeation enhancer.
  • the enhancers chosen for evaluation were hydroxypropyl methylcellulose, poly(vinyl pyrrolidone), and hydroxypropyl cellulose.
  • Coatings were applies to potassium chloride tablets with an Aeromatic ® coater (modified model STREA-1 ).
  • the coating solution contained about 3% solids by weight in a methylene chloride/methanol solvent (80:20 ratio by weight). Mixing times were about two to three hours.
  • TABLE 3 illustrates a general decrease in the pressure required to collapse a poly(lactide-glycolide)/cellulose acetate/poly(ethylene glycol) membrane over a 30 day exposure period to artificial Gl fluid. After 30 days, the collapse pressure of the membrane had dropped over 30%.

Abstract

L'invention concerne une pompe à absorption de fluide utilisant une membrane perméable à l'eau et ayant une intégrité structurelle suffisante pour effectuer l'administration d'un agent. Cette membrane se biodégrade lors de son exposition à des fluides gastrointestinaux et se désintègre dans les 90 jours après l'administration de l'agent. La membrane comprend de préférence un poly(d,l-lactide-co-glycolide) et un polymère hydrophile. L'invention concerne également des procédés de revêtement d'une pompe à absorption de fluide avec des copolymères poly(lactide-glycolide) et des polymères hydrophiles.
PCT/US1994/003394 1993-03-29 1994-03-29 Membrane biodegradable, permeable a l'eau pour pompe a absorption de fluide WO1994022424A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65266/94A AU6526694A (en) 1993-03-29 1994-03-29 Biodegradable, water-permeable membrane for fluid-imbibing pump

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US3785693A 1993-03-29 1993-03-29
US037,856 1993-03-29

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309051A1 (fr) * 1987-09-24 1989-03-29 Merck & Co. Inc. Pompe osmotique à porosité contrôlée
WO1993006819A1 (fr) * 1991-10-10 1993-04-15 Alza Corporation Dispositifs de perfusion osmotique de medicaments utilisant des materiaux de paroi hydrophobes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0309051A1 (fr) * 1987-09-24 1989-03-29 Merck & Co. Inc. Pompe osmotique à porosité contrôlée
WO1993006819A1 (fr) * 1991-10-10 1993-04-15 Alza Corporation Dispositifs de perfusion osmotique de medicaments utilisant des materiaux de paroi hydrophobes

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